Phase 1/2 study of combined BCL-xL and MEK inhibition with navitoclax and trametinib in KRAS or NRAS mutant advanced solid tumors.

PURPOSE:MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS:We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pre-treatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS:91 patients initiated treatment, 38 in dose escalation. 58% had ³3 prior therapies. 15 patients (17%) had colorectal cancer (CRC), 19 (11%) pancreatic, 15 (167%) NSCLC, and 32 (35%) GYN cancers. The recommended phase 2 dose (RP2D) was established as trametinib 2mg daily days 1-14 and navitoclax 250mg daily days 1-28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8/49 (16.3%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In GYN patients at the RP2D, 7/21 (33.3%) achieved a PR and median duration of response 8.2 months. No PRs occurred in CRC, NSCLC, or pancreatic patients. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS:Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.